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1.
Int J Mol Sci ; 24(19)2023 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-37833947

RESUMO

The transition time during which a virus leaves its host and infects the next susceptible host is critical for virus survival. Enterovirus 71 (EV71) is stable in aqueous environments, but its molecular interactions with bacteria and their biofilms are not well-established. Helicobacter pylori is a highly successful gut bacterial pathogen, with its capacity to form biofilms being linked to its transmission. Given that both are gut-associated microbes, we hypothesized that biofilms formed by H. pylori may play a significant role in the survival of EV71 in the external environment. In this study, we examine the interactions of EV71 with the preformed biofilm of H. pylori to mimic its natural state in the environment. Immunofluorescence confocal microscopy and scanning electron microscopy revealed that EV71 particles persisted for up to 10 days when incubated with the H. pylori biofilm. Furthermore, the presence of the H. pylori biofilm significantly augmented viral viability, as verified through virus plaque assays. Interestingly, the viability of EV71 was dependent on the quantity of H. pylori biofilm formation. Thus, two H. pylori strains able to generate large amounts of biofilm could facilitate EV71 viability for up to 17 days, whereas two other H. pylori strains that produced moderate or low quantities of biofilm could not prolong virus viability. It is interesting that biofilm contains N-acetyl-glucosamine and glycosaminoglycan, and that EV71 has binding affinity to cell-surface heparan sulfate glycosaminoglycan, which acts as an EV71 attachment receptor. The synergistic ability of H. pylori biofilm to promote EV71 viability for extended periods implies that H. pylori biofilm may serve as an additional pathway of EV71 transmission.


Assuntos
Enterovirus Humano A , Helicobacter pylori , Viabilidade Microbiana , Biofilmes , Glicosaminoglicanos
2.
Gut ; 71(5): 854-863, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-33975867

RESUMO

OBJECTIVE: To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC. METHODS: A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN). RESULTS: There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori. Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV. CONCLUSIONS: We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Lesões Pré-Cancerosas , Neoplasias Gástricas , Gastroscopia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Humanos , Metaplasia , Lesões Pré-Cancerosas/epidemiologia , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/etiologia
3.
Biomed Mater ; 16(5)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34375969

RESUMO

Combating bacteria while promoting tissue regeneration is an aim of highest priority for employing biomaterials in orthopedics that often embroiled with pre-operative contamination. Through simulating a surgical site infection environment and an infected implant site, we showcase the ability of a functionally modified hydroxyapatite, Ag,Si-HA that permits preferential adhesion of human bone marrow derived mesenchymal stem cells (BMSCs) over co-cultured bacterial pathogen,Pseudomonas aeruginosa, by displaying immediate suppression and killing of the bacteria present with minimum cytotoxicity for 28 d. And, at the same time, Ag,Si-HA stimulates BMSCs towards osteogenic differentiation despite being within the contaminated milieu. These findings provide well-defined requirements for incorporating antibacterial properties to biomaterials in managing pre-operative contamination. In addition, it highlights the dual positive attributes of Ag,Si-HA as an effective antibacterial biomaterial and at the same time, promotes bone tissue regeneration.


Assuntos
Antibacterianos , Durapatita , Osteogênese/efeitos dos fármacos , Silício , Prata , Antibacterianos/química , Antibacterianos/farmacologia , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Técnicas de Cocultura , Durapatita/química , Durapatita/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Silício/química , Silício/farmacologia , Prata/química , Prata/farmacologia
4.
Acta Crystallogr F Struct Biol Commun ; 76(Pt 12): 623, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33263575

RESUMO

The name of the first author in the article by Tulisas et al. [(2009), Acta Cryst. F65, 533-535] is corrected.

5.
Sci Rep ; 8(1): 1409, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362474

RESUMO

The biofilm-forming-capability of Helicobacter pylori has been suggested to be among factors influencing treatment outcome. However, H. pylori exhibit strain-to-strain differences in biofilm-forming-capability. Metabolomics enables the inference of spatial and temporal changes of metabolic activities during biofilm formation. Our study seeks to examine the differences in metabolome of low and high biofilm-formers using the metabolomic approach. Eight H. pylori clinical strains with different biofilm-forming-capability were chosen for metabolomic analysis. Bacterial metabolites were extracted using Bligh and Dyer method and analyzed by Liquid Chromatography/Quadrupole Time-of-Flight mass spectrometry. The data was processed and analyzed using the MassHunter Qualitative Analysis and the Mass Profiler Professional programs. Based on global metabolomic profiles, low and high biofilm-formers presented as two distinctly different groups. Interestingly, low-biofilm-formers produced more metabolites than high-biofilm-formers. Further analysis was performed to identify metabolites that differed significantly (p-value < 0.005) between low and high biofilm-formers. These metabolites include major categories of lipids and metabolites involve in prostaglandin and folate metabolism. Our findings suggest that biofilm formation in H. pylori is complex and probably driven by the bacterium' endogenous metabolism. Understanding the underlying metabolic differences between low and high biofilm-formers may enhance our current understanding of pathogenesis, extragastric survival and transmission of H. pylori infections.


Assuntos
Biofilmes/crescimento & desenvolvimento , Helicobacter pylori/fisiologia , Metabolômica/métodos , Proteínas de Bactérias/metabolismo , Cromatografia Líquida , Helicobacter pylori/metabolismo , Análise de Componente Principal , Espectrometria de Massas em Tandem
6.
Cell Microbiol ; 19(12)2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28776327

RESUMO

Outer inflammatory protein A (OipA) is an important virulence factor associated with gastric cancer and ulcer development; however, the results have not been well established and turned out to be controversial. This study aims to elucidate the role of OipA in Helicobacter pylori infection using clinical strains harbouring oipA "on" and "off" motifs. Proteomics analysis was performed on AGS cell pre-infection and postinfection with H. pylori oipA "on" and "off" strains, using liquid chromatography/mass spectrometry. AGS apoptosis and cell cycle assays were performed. Moreover, expression of vacuolating cytotoxin A (VacA) was screened using Western blotting. AGS proteins that have been suggested previously to play a role or associated with gastric disease were down-regulated postinfection with oipA "off" strains comparing to oipA "on" strains. Furthermore, oipA "off" and ΔoipA cause higher level of AGS cells apoptosis and G0/G1 cell-cycle arrest than oipA "on" strains. Interestingly, deletion of oipA increased bacterial VacA production. The capability of H. pylori to induce apoptosis and suppress expression of proteins having roles in human disease in the absence of oipA suggests that strains not expressing OipA may be less virulent or may even be protective against carcinogenesis compared those expressing OipA. This potentially explains the higher incidence of gastric cancer in East Asia where oipA "on" strains predominates.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas da Membrana Bacteriana Externa/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/fisiologia , Helicobacter pylori/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Western Blotting , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Deleção de Genes , Helicobacter pylori/química , Humanos , Espectrometria de Massas , Proteoma/análise , Fatores de Virulência/análise
7.
Food Microbiol ; 62: 68-76, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27889168

RESUMO

To date, the exact route and mode of transmission of Helicobacter pylori remains elusive. The detection of H. pylori in food using molecular approaches has led us to postulate that the gastric pathogen may survive in the extragastric environment for an extended period. In this study, we show that H. pylori prolongs its survival by forming biofilm and micro-colonies on vegetables. The biofilm forming capability of H. pylori is both strain and vegetable dependent. H. pylori strains were classified into high and low biofilm formers based on their highest relative biofilm units (BU). High biofilm formers survived longer on vegetables compared to low biofilm formers. The bacteria survived better on cabbage compared to other vegetables tested. In addition, images captured on scanning electron and confocal laser scanning microscopes revealed that the bacteria were able to form biofilm and reside as micro-colonies on vegetable surfaces, strengthening the notion of possible survival of H. pylori on vegetables for an extended period of time. Taken together, the ability of H. pylori to form biofilm on vegetables (a common food source for human) potentially plays an important role in its survival, serving as a mode of transmission of H. pylori in the extragastric environment.


Assuntos
Biofilmes/crescimento & desenvolvimento , Microbiologia de Alimentos , Helicobacter pylori/fisiologia , Verduras/microbiologia , Aderência Bacteriana/fisiologia , Brassica/microbiologia , Humanos , Viabilidade Microbiana , Folhas de Planta/microbiologia , Estômatos de Plantas/microbiologia
8.
J Mater Sci Mater Med ; 28(1): 3, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27878735

RESUMO

Prevention of infection and enhanced osseointegration are closely related, and required for a successful orthopaedic implant, which necessitate implant designs to consider both criteria in tandem. A multi-material coating containing 1:1 ratio of silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite as the top functional layer, and hydroxyapatite as the base layer, was produced via the drop-on-demand micro-dispensing technique, as a strategic approach in the fight against infection along with the promotion of bone tissue regeneration. The homogeneous distribution of silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite micro-droplets at alternate position in silicon-substituted hydroxyapatite-silver-substituted hydroxyapatite/hydroxyapatite coating delayed the exponential growth of Staphylococcus aureus for up to 24 h, and gave rise to up-regulated expression of alkaline phosphatase activity, type I collagen and osteocalcin as compared to hydroxyapatite and silver-substituted hydroxyapatite coatings. Despite containing reduced amounts of silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite micro-droplets over the coated area than silicon-substituted hydroxyapatite and silver-substituted hydroxyapatite coatings, silicon-substituted hydroxyapatite-silver-substituted hydroxyapatite/hydroxyapatite coating exhibited effective antibacterial property with enhanced bioactivity. By exhibiting good controllability of distributing silicon-substituted hydroxyapatite, silver-substituted hydroxyapatite and hydroxyapatite micro-droplets, it was demonstrated that drop-on-demand micro-dispensing technique was capable in harnessing the advantages of silver-substituted hydroxyapatite, silicon-substituted hydroxyapatite and hydroxyapatite to produce a multi-material coating along with enhanced bioactivity and reduced infection.


Assuntos
Apatitas/química , Materiais Revestidos Biocompatíveis/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Adipócitos/citologia , Fosfatase Alcalina/metabolismo , Antibacterianos/farmacologia , Regeneração Óssea , Proliferação de Células , Colágeno/química , Humanos , Hidroxiapatitas/química , Nanopartículas Metálicas/química , Testes de Sensibilidade Microbiana , Microscopia Confocal , Osseointegração/efeitos dos fármacos , Osteocalcina/química , Pós , Silício/química , Prata/química , Propriedades de Superfície
9.
PLoS One ; 11(11): e0166835, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27870886

RESUMO

BACKGROUND: Biofilm formation by Helicobacter pylori may be one of the factors influencing eradication outcome. However, genetic differences between good and poor biofilm forming strains have not been studied. MATERIALS AND METHODS: Biofilm yield of 32 Helicobacter pylori strains (standard strain and 31 clinical strains) were determined by crystal-violet assay and grouped into poor, moderate and good biofilm forming groups. Whole genome sequencing of these 32 clinical strains was performed on the Illumina MiSeq platform. Annotation and comparison of the differences between the genomic sequences were carried out using RAST (Rapid Annotation using Subsystem Technology) and SEED viewer. Genes identified were confirmed using PCR. RESULTS: Genes identified to be associated with biofilm formation in H. pylori includes alpha (1,3)-fucosyltransferase, flagellar protein, 3 hypothetical proteins, outer membrane protein and a cag pathogenicity island protein. These genes play a role in bacterial motility, lipopolysaccharide (LPS) synthesis, Lewis antigen synthesis, adhesion and/or the type-IV secretion system (T4SS). Deletion of cagA and cagPAI confirmed that CagA and T4SS were involved in H. pylori biofilm formation. CONCLUSIONS: Results from this study suggest that biofilm formation in H. pylori might be genetically determined and might be influenced by multiple genes. Good, moderate and poor biofilm forming strain might differ during the initiation of biofilm formation.


Assuntos
Proteínas de Bactérias/genética , Biofilmes/crescimento & desenvolvimento , Genômica/métodos , Helicobacter pylori/fisiologia , Proteínas de Bactérias/metabolismo , Genoma Bacteriano , Helicobacter pylori/classificação , Helicobacter pylori/genética , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas In Vitro , Análise de Sequência de DNA
10.
Microbiology (Reading) ; 162(8): 1360-1366, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27283429

RESUMO

Galectin-3 (Gal-3) is a ß-galactoside lectin that is upregulated and rapidly secreted by gastric epithelial cells in response to Helicobacter pylori infection. An earlier study reported the involvement of H. pylori cytotoxin-associated gene A (cagA) in the expression of intracellular Gal-3. However, the role of extracellular Gal-3 and its functional significance in H. pylori-infected cells remains uncharacterized. Data presented here demonstrate secretion of Gal-3 is an initial host response event in gastric epithelial cells during H. pylori infection and is independent of CagA. Previously, Gal-3 was shown to bind to H. pylori LPS. The present study elaborates the significance of this binding, as extracellular recombinant Gal-3 (rGal-3) was shown to inhibit the adhesion of H. pylori to the gastric epithelial cells. Interestingly, a decrease in H. pylori adhesion to host cells also resulted in a decrease in apoptosis. Furthermore, the study also demonstrated a chemoattractant role of extracellular rGal-3 in the recruitment of THP-1 monocytes. This study outlines the previously unidentified roles of extracellular Gal-3 where it acts as a negative regulator of H. pylori adhesion and apoptosis in gastric epithelial cells, and as a chemoattractant to THP-1 monocytes. Our findings could contribute to the better understanding of how Gal-3 acts as a modulator under H. pylori-induced pathological conditions.


Assuntos
Antígenos de Bactérias/metabolismo , Aderência Bacteriana/fisiologia , Proteínas de Bactérias/metabolismo , Quimiotaxia/fisiologia , Células Epiteliais/microbiologia , Galectina 3/metabolismo , Helicobacter pylori/metabolismo , Antígenos de Bactérias/genética , Apoptose/fisiologia , Proteínas de Bactérias/genética , Linhagem Celular Tumoral , Infecções por Helicobacter/patologia , Humanos , Neoplasias Gástricas/patologia
11.
Sci Rep ; 6: 26784, 2016 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-27222005

RESUMO

Helicobacter pylori may reside in the human stomach as two morphological forms: the culturable spiral form and the viable but non-culturable (VBNC) coccoid form. This bacterium transforms from spiral to coccoid under in vitro suboptimal conditions. However, both spiral and coccoid have demonstrated its infectivity in laboratory animals, suggesting that coccoid may potentially be involved in the transmission of H. pylori. To determine the relevance of the coccoid form in viability and infectivity, we compared the protein profiles of H. pylori coccoids obtained from prolonged (3-month-old) culture with that of 3-day-old spirals of two H. pylori standard strains using SWATH (Sequential Window Acquisition of all Theoretical mass spectra)-based approach. The protein profiles reveal that the coccoids retained basal level of metabolic proteins and also high level of proteins that participate in DNA replication, cell division and biosynthesis demonstrating that coccoids are viable. Most interestingly, these data also indicate that the H. pylori coccoids possess higher level of proteins that are involved in virulence and carcinogenesis than their spiral counterparts. Taken together, these findings have important implications in the understanding on the pathogenesis of H. pylori-induced gastroduodenal diseases, as well as the probable transmission mode of this bacterium.


Assuntos
Proteínas de Bactérias/análise , Regulação Bacteriana da Expressão Gênica , Helicobacter pylori/fisiologia , Espectrometria de Massas/métodos , Proteômica/métodos , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Técnicas Bacteriológicas , Parede Celular/metabolismo , Replicação do DNA , DNA Bacteriano/metabolismo , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/genética , Helicobacter pylori/ultraestrutura , Humanos , Redes e Vias Metabólicas , Níquel/farmacologia , Virulência
12.
Cell Biol Toxicol ; 32(1): 23-35, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27044250

RESUMO

Galectin 3 (Gal-3) is upregulated in gastric epithelial cells as a host response to Helicobacter pylori infection. However, the significance of Gal-3 expression in H. pylori-infected cells is not well established. We analyzed Gal-3 intracellular expression, localization, and its effects in H. pylori-infected gastric epithelial cells. The predominantly nuclear confined Gal-3 was shown to be upregulated and exported out to the cytoplasm in H. pylori-infected AGS cells. The nuclear export was channeled through CRM-1 (exportin-1) protein. Interestingly, knock down of Gal-3 expression led to reduced NF-κB promoter activity and interleukin-8 (IL-8) secretion, suggesting its pro-inflammatory roles. Furthermore, Gal-3 was found to be pro-proliferative and anti-apoptotic in nature, as its knock down caused a reduction in cell proliferation and an increase in apoptosis, respectively. Taken together, our data suggest the expression and upregulation of Gal-3 as a critical endogenous event in H. pylori infection that interferes with various intracellular events, causing prolonged cell survival, which is characteristic in carcinogenesis.


Assuntos
Galectina 3/biossíntese , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/patologia , Humanos , Interleucina-8/metabolismo , Carioferinas/metabolismo , NF-kappa B/metabolismo , Transporte Proteico , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Regulação para Cima , Proteína Exportina 1
13.
PLoS One ; 10(6): e0131460, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26111186

RESUMO

Helicobacter pylori causes cellular vacuolation in host cells, a cytotoxic event attributed to vacuolating cytotoxin (VacA) and the presence of permeant weak bases such as ammonia. We report here the role of γ-glutamyl transpeptidase (GGT), a constitutively expressed secretory enzyme of H. pylori, in potentiating VacA-dependent vacuolation formation in H. pylori-infected AGS and primary gastric cells. The enhancement is brought about by GGT hydrolysing glutamine present in the extracellular medium, thereby releasing ammonia which accentuates the VacA-induced vacuolation. The events of vacuolation in H. pylori wild type (WT)- and Δggt-infected AGS cells were first captured and visualized by real-time phase-contrast microscopy where WT was observed to induce more vacuoles than Δggt. By using semi-quantitative neutral red uptake assay, we next showed that Δggt induced significantly less vacuolation in AGS and primary gastric epithelial cells as compared to the parental strain (P<0.05) indicating that GGT potentiates the vacuolating effect of VacA. Notably, vacuolation induced by WT was significantly reduced in the absence of GGT substrate, glutamine (P<0.05) or in the presence of a competitive GGT inhibitor, serine-borate complex. Furthermore, the vacuolating ability of Δggt was markedly restored when co-incubated with purified recombinant GGT (rGGT), although rGGT itself did not induce vacuolation independently. Similarly, the addition of exogenous ammonium chloride as a source of ammonia also rescued the ability of Δggt to induce vacuolation. Additionally, we also show that monoclonal antibodies against GGT effectively inhibited GGT activity and successfully suppressed H. pylori-induced vacuolation. Collectively, our results clearly demonstrate that generation of ammonia by GGT through glutamine hydrolysis is responsible for enhancing VacA-dependent vacuolation. Our findings provide a new perspective on GGT as an important virulence factor and a promising target in the management of H. pylori-associated gastric diseases.


Assuntos
Proteínas de Bactérias/fisiologia , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/enzimologia , Gastropatias/microbiologia , Vacúolos/metabolismo , gama-Glutamiltransferase/fisiologia , Anticorpos Monoclonais/farmacologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Infecções por Helicobacter/patologia , Helicobacter pylori/fisiologia , Humanos , Cultura Primária de Células , Vacúolos/efeitos dos fármacos , Vacúolos/patologia , gama-Glutamiltransferase/imunologia , gama-Glutamiltransferase/farmacologia
14.
Microbiology (Reading) ; 161(6): 1150-60, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25721850

RESUMO

Helicobacter pylori is a major aetiological agent in the development of various gastroduodenal diseases. Its persistence in gastric mucosa is determined by the interaction between various host, microbial and environmental factors. The bacterium colonizes the gastric epithelium and induces activation of various chemokine mediators, including NFκB, the master regulator of inflammation. H. pylori infection is also associated with an increase in expression of cell cycle regulators, thereby leading to mucosal cell hyper-proliferation. Thus, H. pylori-associated infections manifest activation of key host response events, which inadvertently could lead to the establishment of chronic infection and neoplastic progression. This article reviews and elaborates the current knowledge in H. pylori-induced activation of various host signalling pathways that could promote cancer development. Special focus is placed on the inflammatory and proliferative responses that could serve as suitable biomarkers of infection, since a sustained cell proliferation in an environment rich in inflammatory cells is characteristic in H. pylori-associated gastric malignancies. Here, the role of ERK and WNT signalling in H. pylori-induced activation of inflammatory and proliferative responses respectively is discussed in detail. An in depth analysis of the underlying signalling pathways and interacting partners causing alterations in these crucial host responses could contribute to the development of successful therapeutic strategies for the prevention, management and treatment of H. pylori infection.


Assuntos
Helicobacter pylori/fisiologia , Interações Hospedeiro-Patógeno , Inflamação/microbiologia , Sistema de Sinalização das MAP Quinases , Neoplasias Gástricas/microbiologia , Via de Sinalização Wnt , Humanos
15.
Bioorg Med Chem Lett ; 25(3): 607-10, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25544370

RESUMO

A 26-member library of novel N-hydroxyquinolinone derivatives was synthesized by a one-pot Buchwald-type palladium catalyzed amidation and condensation sequence. The design of these rare scaffolds was inspired from N-hydroxypyridones and 2-quinolinones classes of compounds which have been shown to have rich biological activities. The synthesized compounds were evaluated for their anti-plasmodial and anti-bacterial properties. In addition, these compounds were screened for their iron(II)-chelation properties. Notably, four of these compounds exhibited anti-plasmodial activities comparable to that of the natural product cordypyridone B.


Assuntos
Amidas/química , Antibacterianos/síntese química , Antimaláricos/síntese química , Quelantes/síntese química , Compostos Ferrosos/química , Quinolonas/química , Antibacterianos/química , Antibacterianos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Catálise , Quelantes/química , Quelantes/farmacologia , Ciclização , Escherichia coli/efeitos dos fármacos , Paládio/química , Plasmodium/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
16.
Int Rev Immunol ; 33(6): 443-53, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24911430

RESUMO

Cross-talk within the innate immune pathways is highly complex and contains many unknowns. Here, we discuss the different combinations of PAMPs, together with the sequence, order, and dosage of consecutive PAMP challenges, which determine the nature of the immune response by macrophages. The engagement of different Toll-like receptor (TLR) ligands leads to quantitatively and qualitatively unique cytokine production, showing that TLR pathway crosstalk enables the innate immune system to orchestrate immediate local and global responses. It is likely that multiple pathways are involved in the regulation of cytokine synergy, including many that have yet to be discovered.


Assuntos
Macrófagos/imunologia , Transdução de Sinais , Receptores Toll-Like/agonistas , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata , Ligantes , Receptor Cross-Talk
17.
J Innate Immun ; 6(4): 515-29, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24685988

RESUMO

Hemolysis releases hemoglobin (Hb), a prooxidant, into circulation. While the heme iron is a nutrient for the invading pathogens, it releases ROS, which is both microbicidal and cytotoxic, making it a double-edged sword. Previously, we found a two-pass detoxification mechanism involving the endocytosis of Hb into monocytes in collaboration with vascular endothelial cells to overcome oxidative damage. This prompted us to examine the effect of Hb priming on host cell viability and intracellular bacterial clearance during a hemolytic infection. Here, we demonstrate that Hb-primed macrophages harbor a higher intracellular bacterial load but with suppressed apoptosis. p-ERK and p-p38 MAPK were significantly downregulated, with concomitant impairment of Bax and downstream caspases. The Hb-primed cells harboring intracellular bacteria upregulated anti-inflammatory IL-10 and downregulated proinflammatory TNF-α, which further enhanced the infectivity of the neighboring cells. Our findings suggest that opportunistic intracellular pathogens exploit the Hb-scavenging machinery of the host to silently persist within the circulating phagocytes by suppressing apoptosis while escaping immune surveillance.


Assuntos
Apoptose , Infecções Bacterianas/imunologia , Hemoglobinas/farmacologia , Macrófagos/imunologia , Oxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carga Bacteriana/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hemólise/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Espaço Intracelular , Macrófagos/microbiologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Biomed Mater ; 9(1): 015010, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24448654

RESUMO

An integrated approach is proposed to incorporate silicon and silver into hydroxyapatite (HA) to enhance the biological response and reduce implant-related infection in bone substitutes. This study examined the responses of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) bacteria to silver, silicon-containing apatite (Ag,Si-HA). Scanning electron microscopy images revealed significant reduction in adherence of S. aureus and E. coli bacteria on Ag,Si-HA as compared to HA. The antibacterial property of Ag,Si-HA was shown from a 7-log reduction of S. aureus population in the test solution and on the sample's surface as compared to HA at day 7. Rapid inhibition of the adherent bacteria suggested that the antibacterial action of Ag incorporated in Ag,Si-HA could be attributed to the Ag(+) ions on the crystal surface rather than the released Ag(+) ions. Presence of Ag may influence the biological response of HA and as such, the long-term interaction between human adipose-derived mesenchymal stem cells and Ag,Si-HA was evaluated in-vitro. An alamarBlue™ assay showed higher cell proliferation for Ag,Si-HA as compared to HA from day 3 onwards. Immunofluorescence staining revealed well-spread actin cytoskeletons on Ag,Si-HA. In addition, signs of extracellular matrix secretion and biomineralization were observed on Ag,Si-HA at day 14 onwards. Results demonstrated enhanced bone differentiation on Ag,Si-HA, as indicated by a higher level of protein expressions (type 1 collagen and osteocalcin) from day 14 to 21. Therefore, the incorporation of Ag and Si complement each other by endowing HA with antibacterial property, and concurrently promoting biological performance of the cells.


Assuntos
Durapatita/química , Silício/química , Prata/química , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/microbiologia , Antibacterianos , Diferenciação Celular , Colágeno Tipo I/metabolismo , Citoesqueleto/metabolismo , Escherichia coli/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Íons , Teste de Materiais , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/microbiologia , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência , Osteocalcina/metabolismo , Staphylococcus aureus/efeitos dos fármacos
19.
J Mater Chem B ; 2(12): 1706-1716, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32261400

RESUMO

Bacterial colonization of urinary catheters is a common problem leading to Catheter Associated Urinary Tract Infections (CAUTIs) in patients, which result in high treatment costs and associated complications. Due to the advantages of antimicrobial peptides (AMPs) compared to most other antimicrobial molecules, an increasing number of AMP-coated surfaces is being developed but their efficacy is hindered by suboptimal coating methods and loss of peptide activity upon surface tethering. This study aims to address this issue by employing a methodic approach that combines a simple selective chemical immobilization platform developed on a silicone catheter with the choice of a potent AMP, Lasioglossin-III (Lasio-III), to allow site specific immobilization of Lasio-III at an effective surface concentration. The Lasio-III peptide was chemically modified at the N-terminal with a cysteine residue to facilitate cysteine-directed immobilization of the peptide onto a commercial silicone catheter surface via a combination of an allyl glycidyl ether (AGE) brush and polyethylene glycol (PEG) based chemical coupling. The amount of immobilized peptide was determined to be 6.59 ± 0.89 µg cm-2 by Sulfo-SDTB assay. The AMP-coated catheter showed good antimicrobial activity against both Gram positive and negative bacteria. The antimicrobial properties of the AMP-coated catheter were sustained for at least 4 days post-incubation in a physiologically relevant environment and artificial urine and prevented the biofilm growth of E. coli and E. faecalis. Adenosine tri-phosphate leakage and propidium iodide fluorescence studies further confirmed the membranolytic mode of action of the immobilized peptide. To the best of our knowledge, this is the first proof-of-concept study that reports the efficacy of AMP immobilization by sulfhydryl coupling on a real catheter surface.

20.
World J Gastroenterol ; 19(45): 8203-10, 2013 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-24363510

RESUMO

Helicobacter pylori (H. pylori) produce an enzyme known as γ-glutamyl transpeptidase (HpGGT) that is highly conserved and common to all strains. HpGGT has been gaining increasing attention as an important virulence factor of the bacterium, having been demonstrated to be an important colonization factor in several animal models and has also recently been strongly associated with the development of peptic ulcer disease. From the results of various independent researcher groups, it is clear that HpGGT acts through several pathways to damage gastric epithelial cells including the induction of apoptosis and cell cycle arrest, production of reactive oxygen species leading to DNA damage, promotion of inflammation by increasing cyclooxygenase-2 and interleukin-8 expression, and upregulation of heparin-binding epidermal growth factor-like growth factor resulting in cell survival and proliferation. In addition, the potential role of HpGGT in promoting gastric carcinogenesis will also be discussed in this review. Apart from affecting the gastric epithelium, HpGGT also has immunomodulatory actions on host immune cells where it displays an antiproliferative effect on T cells by inducing cell cycle arrest and also works with other H. pylori virulence factors to skew dendritic cells towards a tolerogenic phenotype, possibly contributing to the persistence of the pathogen in the gastric mucosa.


Assuntos
Proteínas de Bactérias/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/enzimologia , Fatores de Virulência/metabolismo , gama-Glutamiltransferase/metabolismo , Animais , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Prognóstico , Fatores de Risco , Transdução de Sinais , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia
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